The pancreas is an organ constituted by endocrine gland tissues called the pancreas islets (Langerhans islets) and exocrine gland tissues secreting digestive enzymes. The β cells, α cells, δ cells, pancreatic polypeptide cells, and so forth exist in the Langerhans islets, and they greatly affect the control of blood glucose and metabolism. Among these, the β cells play a particularly important role as cells producing insulin.
Diabetes mellitus is a highly frequently observed metabolic disorder recognized in 10% of Japanese adults. According to the epidemiology of the β cell dysfunction of the pancreas, which is considered one of the causes of diabetes mellitus, while the β cell dysfunction is of course observed in individuals with borderline type hyperglycemia, individuals exhibiting normal glucose tolerance also include individuals exhibiting clearly reduced β cell functions at a rate of 30%. Moreover, it is said that adults who lead average social life in present-day Japan highly frequently causes insulin resistance more or less, and it is considered that, as for persons suffering from insulin resistance, in those who do not suffer from β cell dysfunction, the blood glucose level does not increase, and in those who suffer from β cell dysfunction, the blood glucose level increases from a level corresponding to normal glucose tolerance to a level corresponding to borderline type hyperglycemia (Non-patent document 1).
At present, although therapies for promoting spontaneous recovery of the pancreatic functions based on removal of causative pathological conditions or factors are used for pancreatic function disorder, any therapeutic method or agent for positively restoring pancreatic functions once degraded has not been used so far, and agents for protecting pancreatic cells or agents for improving damaged pancreatic cells are desired in the clinical field.
The pancreatic function disorder means a pathological condition that the endocrine or exocrine gland functions of the pancreas are lowered or abnormally enhanced.
As the prior art of agents for curing pancreatic function disorder, those containing neurotrophic factors such as BDNF as an active ingredient (Patent document 1), those containing glycerol derivatives as an active ingredient (Patent document 2), pancreatic function improving agents containing betacellulin proteins or muteins thereof (Patent document 3), and so forth. It has been so far considered that BDNF is released from the central end of small DRG neuron with other transmitters at the time of inflammation or nerve damage, and involved in promotion of pain signal transduction via tyrosine phosphorylation of the NMDA receptor on the dorsal horn cells (Non-patent document 2), and thus it is considered to be restricted for actual use.
Further, the glycerol derivatives disclosed in Patent document 2 are the compounds described in Patent document 4, and are agents having antiplatelet-activating factor (PAF) activity for therapeutic and prophylactic treatment of DIC, shock, allergy, acute pancreatitis, brain twitch at the time of subarachnoid haemorrhage, and so forth, and they are also found to have an organopathy preventing, curing and improving effect for preventing, curing and improving organopathy caused in processes of preservation of organ in ischemic condition, blood flow obstruction caused by post-graft blood reperfusion or surgery, and so forth. However, it is hard to say that these agents are suitable for chronic pancreatic diseases without these symptoms.
Moreover, the pancreatic function improving agents containing betacellulin proteins or muteins thereof disclosed in patent document 3 also have an action of acting on undifferentiated pancreatic stem cells and thereby promoting differentiation of them into the pancreatic β cells producing insulin, and an action of inducing differentiation of undifferentiated stem cells into other cells of the pancreas such as F cells producing pancreatic polypeptides, and the effect cannot be expected under a condition that immature cells are depleted. In addition, although mRNAs of these proteins are detected in various organs other than the brain, for example, liver, kidney, pancreas, etc., the details of the functions thereof are not clarified almost at all, and therefore it cannot be said that they can be immediately used for clinical cases.
Furthermore, it has been disclosed in patent document 5 that compounds having a lanostane skeleton or 3,4-secolanostane skeleton have an insulin action enhancing activity. The effect of these compounds is to enhance the insulin action in regulation of adipocyte differentiation, and the effect thereof on pancreatic diseases remains unknown.
Furthermore, as the prior arts concerning compounds having the cyclolanostane skeleton, a method for producing cyclobranol or cyclobranol ferulic acid ester (Patent document 6) as well as tranquilizers (Patent document 7), hypolipidemic drugs (Patent document 8), interferon inducers (Patent document 9), ovulation inducing agents (Patent document 10) and oncogenesis preventive drugs (Patent document 11) containing 24-methylenecycloartanol as an active ingredient have been disclosed. Further, it has not been reported so far that the compounds having the cyclolanostane skeleton have pancreatic function protecting action or pancreatic tissue protecting action.
The genus Aloe in the family Liliaceae is a group of plants including Aloe vera (Aloe barbadensis Miller), Aloe arborescens (Aloe arborescens Miller var. natalensis Berger) and so forth, and they are empirically known to have various efficacies. The prior arts regarding the use of plants of the genus Aloe include immunomodulating polysaccharides (Patent document 12), immunosuppression improving agents containing a butanol fraction of an aloe extract or aloin (Patent document 13), HSP60 family protein synthesis suppressing agents containing aloin derivatives (Patent documents 14 to 16), proteins having lectin activity derived from aloe leaf-skin (Patent document 17), use for improvement of blood glucose levels (Non-patent document 3 to 5, Patent document 18 to 21) and so forth.    [Patent document 1] International Publication No. WO 00/62796    [Patent document 2] Japanese Patent Laid-open No. 07-285866    [Patent document 3] Japanese Patent Laid-open No. 09-188630    [Patent document 4] Japanese Patent Laid-open No. 10-045604    [Patent document 5] Japanese Patent Laid-open No. 10-330266    [Patent document 6] Japanese Patent Laid-open No. 50-160262    [Patent document 7] Japanese Patent Laid-open No. 55-153719    [Patent document 8] Japanese Patent Laid-open No. 59-027824    [Patent document 9] Japanese Patent Laid-open No. 59-036623    [Patent document 10] Japanese Patent Laid-open No. 59-073600    [Patent document 11] Japanese Patent Laid-open No. 2003-277269    [Patent document 12] International Patent Application Unexamined Publication in Japanese No. 2001-520019    [Patent document 13] Japanese Patent Laid-open No. 08-208495    [Patent document 14] Japanese Patent Laid-open No. 10-120576    [Patent document 15] Japanese Patent Laid-open No. 10-045604    [Patent document 16] Japanese Patent Laid-open No. 10-036271    [Patent document 17] Japanese Patent Laid-open No. 09-059298    [Patent document 18] Japanese Patent Laid-open No. 60-214741    [Patent document 19] Japanese Patent Laid-open No. 2003-286185    [Patent document 20] U.S. Pat. No. 4,598,069    [Patent document 21] U.S. Patent Application Publication No.    [Non-patent document 1] Nippon Rinsho, No. 748, Vol. 1, pp. 615-617, 1999    [Non-patent document 2] Nippon Rinsho, No. 808, Vol. 2, pp. 405-409, 2002    [Non-patent document 3] Phytomedicine, Vol. 3, pp. 245-248, 1996    [Non-patent document 4] Phytotherapy Research, Vol. 15, pp. 157-161, 2001    [Non-patent document 5] Phytotherapy Research, Vol. 7, pp. 37-42, 1993